Pathogenic microbes, including bacteria, fungi, protozoae, and viruses, have a profound effect on human health and well-being. In particular, bacterial and fungal infections are known to cause myriad human disorders, ranging from systemic and life-threatening diseases such as tuberculosis and pneumonia, to localized, discomfort-causing and appearance-altering conditions such as acne. The identification of therapeutic compounds useful in the treatment of microbial infections of all severities and modalities is a long-standing and potentially never-ending goal of medicine and pharmacology, made all the more difficult by the resistance of certain microbes to pharmaceutical inactivation. Certain anti-microbial agents are proposed in Hanson, Nat. Prod. Rep., 13, 59-71 (1996); Banthorpe et al., Phytochem. 29(7), 2145-2148 (1990); and Ulubelen et al., Phytochem., 36(4), 971-974 (1994). Dermatological infections and disorders, in particular, may be contrary to effective treatment with pharmaceutical or cosmetic compounds in view of the barrier function of the skin and the difficulty of drug or cosmetic absorption thereby.
Although there are several factors that are thought to cause the skin disorder generally known as acne, one known causative factor is the presence of bacteria in the follicular canal of the skin. Within the follicular canal are bacteria which are indigenous to the follicular lining. One example of this bacteria is the anaerobic, gram positive Propionibacterium acnes. It is thought that P. acnes lives in symbiosis on the keratin lined follicular canal. P. acnes ingests the sebum produced from the sebocytes of the sebaceous glands. This nascent sebum is largely lipid in composition and also contains DNA, RNA, proteins, and other cellular components that result from the breakdown of sebocytes themselves. The P. acnes organisms, which are highly lipophilic, feed on the nascent sebum. It has been shown that P. acnes is found only in sebaceous-rich areas. If the nutrients increase due to an active and large sebaceous system, then colonization and high growth rates of P. acnes will occur. Resident bacterial flora will produce biologically active molecules such as histamine, extracellular enzymes, and peptides which may be responsible for the chemotaxis of the inflammatory infiltrate in acne vulgaris. Since the follicular lining in the pilosebaceous unit is intact, it has been theorized that if colonization of P. acnes occurs in sufficient numbers, they may produce initiating autogenic molecules that promote the initiating of inflammation. P. acnes can produce proteinases, lipase, and hyaluronate lyase all of which may serve as the catalysts or initiators of the inflammatory infiltrate, which has been shown to be composed of neutrophils and lymphocytes.
Gram negative acne, sometimes called gram negative folliculitis when it extends to the neck, arms, legs, and trunk, is a form of an inflammatory papular, follicular, and pustular response to gram negative organisms including Enterobacter, Klebsiella, Escherichia, Proteus, Serratia, and Pseudomonas. The most characteristic lesion on the face is superficial pustules, or papulo-pustules (which is a combination of a papule and pustule). The face can show diffuse erythema and inflammation surrounding these pustules and juicy papules or papulo-pustules. Gram negative acne is usually highly resistant and usually occurs in patients who have bad inflammatory papular acne for long periods or who have been treated with long term oral administration of antibiotics such as tetracycline, erythromycin, or minocycline or topical antibiotics such as topical clindamycin or topical erythromycin. Subsequent to the oral administration tetracycline or erythromycin, oral administration of amoxicillin, ampicillin, and trimethoprin-sulfomethoxazole has been shown to be effective in treating this disease. Poli, F., Prost, C., Revuz, J., Gram-negative Folliculitis, Ann. Dermatol. Venereol., 115:797-800, 1988.
A number of topical and systemic therapeutic treatments are presently known for treating acne. Some of the topical treatments that are presently employed are: topical erythromycin, clindamycin, benzoyl peroxide, sulfur, resorcinol, sulfosalicylate, salicylic acid, and retinoin (Retin-A.RTM.).
Benzoyl peroxide, (C.sub.6 H.sub.5 CO).sub.2 O.sub.2 ("BZP"), is a potent nontoxic oxidant which has long been used for treatment of dermatological lesions and known to be an effective anti-microbial and anti-keratolytic agent useful, for example, in the treatment of acne. Difficulties noted with BZP preparations have included BZP chemical instability. In its particulate solid form, BZP has been found to be generally more stable than its dissolved form. However, when a preparation containing BZP particles is utilized to treat dermatological lesions, the BZP particles eventually contacting the skin may have adverse irritative effects. These adverse effects appear to result, at least in part, from the excessive concentrations of BZP at skin areas in contact with BZP particles. Methods of avoiding such adverse effects while still effectively utilizing BZP therapeutically are long-sought. Still other topical treatments for acne using anti-bacterials are described in the following U.S. patents: an azole derivative in conjunction with benzoyl peroxide, U.S. Pat. No. 4,446,145, and metronidazole in a special gel as described in U.S. Pat. No. 4,837,378.
Aside from treatments mentioned above, some additional systemic treatments for acne that are presently employed are: oral tetracycline; oral erythromycin; minocycline; doxycycline; oral trimethoprim-sulfamethoxazole and isotretinoin (ACCUTANE.RTM.).
It would be desirable to provide methods of providing antimicrobial (e.g., antibacterial and antifungal) treatment, as well as treatment for other conditions and disorders caused by other mechanisms to subjects in need of such treatment, and cosmetic and pharmaceutical formulations useful in such treatments.